The original project was GM 068968, responding to Joint DMS/NIGMS Initiative to Support Research in Mathematical Biology, PA NSF 02-125. This competing renewal application is continues to propose new mathematical innovations in biomedical computational science and technology. Modeling the pharmacokinetic and pharmacodynamic (PK/PD) behavior of drugs has serious statistical flaws. The PK/PD community still uses mainly parametric methods of modeling based on approximate likelihoods, with no guarantee that studying more subjects will obtain parameter estimates closer to the true values (they often get worse). In contrast, our laboratory has developed methods, both parametric (P) and nonparametric (NP), which are statistically consistent. However, there is still no way to obtain rigorous confidence intervals on P or NP parameter estimates. This is a great weakness. Also, current dosing policies are based only on information available now, though we know we will monitor the patient and adjust dosage in the future. These known future actions are ignored. Our aims are (1) TO DEVELOP A NEW SEQUENTIAL BAYESIAN METHOD FOR MAKING PK/PD POPULATION MODELS. We propose an exciting new method to obtain rigorous confidence intervals for parameter estimates for both P and NP population PK/PD models. It is an outgrowth of our previous work in GM 068968. It should also provide rigorous confidence intervals on a clinician's ability to hit a desired therapeutic target serum concentration. This will provide a firm mathematical foundation for all population modeling, and for our current work to optimize coordinated combination drug therapy for which we have recently been funded under grant EB 005803. It is also sequential, and thus permits new subjects to be added to a model rather than having to remake it from scratch. This will greatly aid community hospitals to add their own patients to the original model as desired. (2) TO CONTINUE WORK ON OUR ACTIVE CONTROL STRATEGY TO OPTIMIZE LEARNING ABOUT THE PATIENT WHILE TREATING HIM/HER AT THE SAME TIME. Current dosage regimens use only information available up to now. We know we will monitor the patient and adjust dosage in the future. This is ignored. The dosage regimen is not designed to aid in learning about the patient. We now propose to use the dosage regimen as an active partner in the learning process, by calculating how far (and safely) one can deviate a bit from the target goal to probe the patient's system thoughtfully to learn more about it, and thus to maximize therapeutic precision over the projected duration of therapy. We propose to explore future clinical scenarios in advance, now. Our approach is to approximate the Stochastic Dynamic Programming (SDP) equations of Bellman using the IPS (Iteration in Policy Space) algorithm, and a Particle Filter to solve the underlying nonlinear estimation problem. This should make patient care still more intelligent and optimal. PERFORMANCE SITE(S) (organization, city, state) University of Southern California, Keck School of Medicine, Los Angeles, California PHS 398 (Rev. 04/06) Page 2 Form Page 2 Principal Investigator/Program Director (Last, First, Middle): Jelliffe, Roger WoodhaiD KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information Start with Principal Investigator(s). List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Jelliffe, Roger Jelliffe Univ Southern Calif Bayard David Jet Propulsion Lab Botnen Andreas University of Oslo Schumitzky Alan Univ Southern Calif Van Guilder Michael Univ Southern Calif in the format shown below. Role on Project PI Consultant Consultant Co-Investigator Syst Analyst OTHER SIGNIFICANT CONTRIBUTORS Name Organization Role on Project Human Embryonic Stem Cells [X] No \_\ Yes If the proposed project Involves human embryonic stem cells, list below the registration number of the specific cell llne(s) from the following list: http://stemcells.nih.gov/reaistrv/index.asp. Use continuation pages as needed. Ifaspecificlinecannotbereferencedatthistime,includeastatementthatonefromtheRegistrywillbeused. Cell Line PHS 398 (Rev. 04/06) Page 3 Form Page 2-continued Number the following pages consecutively throughout the application. Do not use suffixes such as 4a, 4b. Principal Investigator/Program Director (Last, First, Middle): Jelliffe, Roger Woodham The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description, Performance Sites, Key Personnel, Other Significant Contributors, and Human Embryonic Stem Cells 2-3 Table of Contents Detailed Budget for Initial Budget Period (or Modular Budget) Budget for Entire Proposed Period of Support (not applicablewith Modular Budget) BudgetsPertainingtoConsortium/ContractualArrangements(notapplicablewithModularBudget) Biographical Sketch - Principal Investigator/Program Director (Not to exceed four pages) 6-8 Other Biographical Sketches (Not to exceed four pages for each - See instructions) 9-18 Resources 19-21 Research Plan. 22 Introduction to Revised/Resubmission Application (Not to exceed 3 pages.)... Introduction to Supplemental/Revision Application (Not to exceed one page.).. A. Specific Aims , 22-23 B. Background and Significance , 23-28 C. Preliminary Studies/Progress Report (Items A-D: not to exceed 25 pages). 28-38 D. Research Design and Methods 38-51 E. Human Subjects Research 52 Protection of Human Subjects (Required if Item 4 on the Face Page is marked 'Yes) Data and Safety Monitoring Plan (Required if Item 4 on the Face Page is marked Yes and a Phase I, II, or III clinical trial is proposed) Inclusion of Women and Minorities (Required if Item 4 on the Face Page is marked Yes and Is Clinical Research) Targeted/Planned Enrollment Table (for new and continuing clinical research studies) Inclusion of Children (Required if Item 4 on the Face Page is marked Yes) F. Vertebrate Animals G. Select Agent Research 52 H. Literature Cited I. Multiple PI Leadership Plan J. Consortium/Contractual Arrangements 57 K. Resource Sharing 57 L. Letters of Support (e.g., Consultants) 58-59 Checklist. 60 Appendix (Five collated sets. No page numbering necessary for Appendix.) Check if Appendix is Included Number of publications and manuscripts accepted for publication (not to exceed 10) Other items (list): PHS 398 (Rev. 04/06) Page 4 Form Page 3